1. Field of the Invention
This invention relates to polymers of lactide and glycolide. More particularly, this invention relates to copolymers of lactide and glycolide having high glycolide content.
2. Related Art
Polymers of lactide and glycolide, and copolymers thereof, have long been known for their susceptibility to degradation by ester hydrolysis in aqueous environments. This property of these polymers has made them attractive for such medical applications as biodegradable surgical sutures; biodegradable rods, pins, and films for setting bone fractures; and as biodegradable polymer matrices for sustained, controlled active agent delivery. Consequently, research has been conducted into the manipulation of the polymers"" degradation properties in order to control degradation times and active agent release rates.
Copolymers of lactide and glycolide have lactate and glycolate monomers. Polymers of lactate and glycolate can be obtained by polycondensation of lactic acid and glycolic acid with or without a catalyst (see, e.g., U.S. Pat. No. 4,157,437, the entirety of which is incorporated herein by reference); however, higher molecular weight polymers (i.e., those with molecular weights greater than a few thousand daltons) can be produced by starting with lactide and glycolide, which are the dioxane dimers of the acids. Production methods of lactide and glycolide are well known in the art (see Sorensen et al., Preparative Methods of Polymer Chemistry, Wiley, N.Y. (1968) and U.S. Pat. No. 4,797,468, both incorporated in their entireties herein by reference). One such method takes polymers of lactate obtained by polycondensation of lactic acid, and decomposes them under heat and reduced pressure, producing lactide (3,6-dimethyl-1,4-dioxane-2,5-dione, formula I): 
Similar methods are known to those skilled in the art for the production of glycolide (1,4-dioxane-2,5-dione, formula II): 
Use of glycolide and lactide as starting materials for the polymerization allows the synthesis of polymers with greater molecular weights than can be synthesized using glycolic acid and lactic acid as starting materials. The ring-opening polymerization reactions can be carried out in bulk or in solution. The polymerization is allowed to proceed for several hours at temperatures between about 150xc2x0 C. and 250xc2x0 C. if done in bulk (above the melting points of the monomers and the polymer to be synthesized), and at significantly lower temperatures (xcx9c50xc2x0 C.) if done in solution. The polymerization proceeds under a reduced pressure of around 1-10 mm Hg or with a dry gas purge (e.g., nitrogen or argon), and in the presence of a catalyst (0.001 to 1% by weight) and a polymerization regulator (0.01 to 0.22 mol % of the monomer) (see, e.g., U.S. Pat. Nos. 4,157,437; 4,797,468; 4,767,628; 4,849,228; 4,859,763; 5,320,624; 5,952,405; 5,968,543; 6,004,573; 6,007,565; Wang et al., J. Biomater. Sci. Polymer Edn. 8(12): 905-17 (1997) (herein referred to as Wang et al., part I); Wu, Encyclopedic Handbook of Biomaterials and Bioengineering (Donald L. Wise, ed.) (Marcel Dekker, Inc., N.Y. 1995) (herein referred to as Wu), all of which are incorporated herein by reference in their entireties). Lewis acids are used to catalyze the polymerization, and stannous octoate (stannous 2-ethylhexanoate) is the most commonly used catalyst (U.S. Pat. No. 4,677,191, the entirety of which is incorporated herein by reference, reports copolymerization of lactic acid and glycolic acid in the absence of a catalyst). Typical polymerization regulators include monohydric, aliphatic, straight chain alcohols.
The copolymerization reaction can be represented symbolically as follows: 
where i represents an oligomer within the polymer containing mi lactate units and ni glycolate units; mi and ni are the block lengths of lactate and glycolate within the ith oligomer. For a polymer composed of N such oligomers, the sum of mi and ni over all of the oligomers i, divided by N gives the average block lengths of lactate units and glycolate units respectively. The average block lengths of lactate and glycolate can be measured using 13C-NMR techniques known to those skilled in the art. The lactide/glycolide mole ratio can be measured using proton NMR techniques known to those skilled in the art.
The molecular weight of a copolymer of lactide and glycolide is one of the characteristics determinative of its degradation rate, with lighter copolymers having greater degradation rates than heavier copolymers (see Wang et al., J. Biomater. Sci. Polymer Edn. 9(1): 75-87 (1997) (herein referred to as Wang et al. part II), the entirety of which is herein incorporated by reference). One method known to those skilled in the art for determining the molecular weights of polymers is to measure their intrinsic viscosity in a solvent of the polymers, where greater intrinsic viscosity corresponds to a greater molecular weight.
Glycolide is more amenable to addition to a growing polymer chain than is lactide (see Gilding et al., Polymer 20: 1459-1464 (1979) (herein referred to as Gilding et al.), the entirety of which is incorporated herein by reference). Gilding et al. report that glycolide is three times more likely to be added to the end of a polymer than lactide if the growing group is a glycolide, and five times more likely if the growing group is a lactide. Therefore, all else being equal, the polymerization reaction will naturally favor copolymers with high glycolide content and blocks of glycolide separated by single lactide units (see Wu).
Glycolide-rich copolymers (i.e., copolymers of lactide and glycolide containing at least 50 mol. % glycolide) degrade faster than lactide-rich copolymers. (see U.S. Pat. No. 4,156,437; Lewis, Biodegradable Polymers as Active agent Delivery Systems (Chasin et al., eds.) (Marcel Dekker, Inc., N.Y. 1990) (herein referred to as Lewis); Park, Biomaterials 16: 1123-30 (1995) (herein referred to as Park), the entirety of each of which is incorporated herein by reference). It has been hypothesized that these greater degradation rates of glycolide-rich copolymers relative to lactide-rich copolymers stems from the hydrophilicity of glycolic acid relative to lactic acid (lactic acid contains a non-polar methane group, making it more hydrophobic) (see, e.g., Wang et al. part II). The greater hydrophilicity of glycolic acid allows the polymer to hydrate more easily, thus allowing access to the ester bonds of the polymer backbone by water. Since degradation of the polymer occurs by hydrolysis of the ester bonds, water""s easier access to the ester bonds results in a more rapid degradation of the polymer (see Park). However, along with the ease of hydration of glycolide-rich copolymers comes another consequence of glycolide""s hydrophilicity: the difficulty of dissolving the glycolide-rich copolymer in slightly polar solvents such as methylene chloride. This difficulty must be overcome in order to use glycolide-rich copolymers in the production of active agent-loaded microparticles.
A significant problem with lactide/glycolide copolymers with high glycolide content is their low solubility in slightly polar solvents such as methylene chloride (see Bendix, Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 17:248-49 (1990) (referred to herein as Bendix), the entirety of which is incorporated herein by reference; see also Wu and Gilding et al.). This problem prevents use of standard solution polymerization and standard purification techniques. An example of a standard purification technique is to dissolve the polymer in methylene chloride and then to pour the polymer solution into methanol. The polymer precipitates, leaving impurities such as unreacted monomers, catalyst and regulator behind. For copolymers rich in glycolide, the choices of polymer solvents (methylene chloride in the example) and polymer non-solvents (methanol in the example) is limited. (For another approach to purifying the polymer, see U.S. Pat. No. 4,849,228, the entirety of which is incorporated herein by reference.) These limitations caused by the insolubility of glycolide-rich copolymers in slightly polar solvents are significant not only to the problems of polymerization and purification, but are also strongly felt in attempts to use these copolymers as matrices for controlled release of active agents because many of the techniques for making controlled release formulations require the polymer to be dissolved in a slightly polar solvent. Thus, there is a need in the art for a glycolide-rich copolymer that can be readily dissolved in slightly polar solvents, such as methylene chloride.
The present invention relates to copolymers of lactide and glycolide with high glycolide content (at least 50% glycolide) that are soluble up to about 40% (m/v) in methylene chloride, and to methods of making these copolymers. In one aspect of the invention, a copolymer having 40-50 mole percent lactide and 50-60 mole percent glycolide is provided that is soluble in methylene chloride in an amount greater than about 10%. In another aspect of the invention, the high glycolide content copolymer has an average glycolate block length of less than about 3. In a further aspect of the invention, the high glycolide content copolymer has an inherent viscosity in chloroform of between 0.07-0.5 dL/g.
Another aspect of the present invention provides block copolymers comprising the glycolide-rich copolymers of glycolide and lactide of the present invention and another polymer or copolymer. These block co-polymers can be tailored to have specific mechanical and degradation properties through selection of the other polymer or copolymer.
Another aspect of the present invention provides graft copolymers comprising the glycolide-rich copolymers of glycolide and lactide of the present invention grafted to the backbone of another polymer or copolymer. These graft co-polymers can be tailored to have specific mechanical and degradation properties through selection of the other polymer or copolymer.
Another aspect of the present invention provides a sustained release active agent delivery system comprising a high glycolide content copolymer that is a biodegradable matrix for an active agent. A wide range of active agents can be incorporated into controlled release devices using the copolymers of the present invention. Preferred active agents for use with the copolymers of the present invention include human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), and analogs of LHRH, insulin, antiinflammatory compounds, and anesthetic compounds. A further aspect of the invention is an active agent delivery system wherein the high glycolide copolymer is dissolved in methylene chloride during the preparation process.
The present invention also provides a method of making high glycolide content copolymers comprising making a mixture comprising D,L-lactide, glycolide, glycolic acid and stannous octoate, and heating the mixture to a temperature between about 175xc2x0 C. and about 220xc2x0 C. Alternatively, instead of the racemic D,L-lactide, optically active L-lactide or D-lactide may be substituted. In a further aspect of the invention, glycolic acid is present in the reaction mixture in an amount of about 0.3% to about 5% of the total monomer weight. In yet a further aspect of the invention, stannous octoate is present in the reaction mixture in an amount of about 0.005% to about 0.06% of the total monomer weight. In a still further aspect of the invention, D,L-lactide is present in an amount between about 40% and 50%, and glycolide is present in an amount between about 50% and 60% of the total monomer weight.
A feature of the present invention is that the copolymers of lactide and glycolide have a high glycolide content, and therefore also have the accompanying degradation properties of a high glycolide content copolymer. Yet these copolymers have the advantage over other high-glycolide copolymers of being substantially soluble in slightly polar solvents. This allows the copolymers to be used in the most common methods for producing sustained release active agent/polymer microparticles.